Even while on current therapies, malaria patients remain infectious for a period of time, allowing further mosquito-borne transmission to others. Control of parasite transmission is critical for elimination and eradication of malaria. However, most antimalarial drugs are not active against sexual stage P. falciparum parasites called gametocytes which are responsible for the spread of malaria from person to person via mosquitoes. To begin to fill this void, investigators screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity. One compound with favorable pharmacokinetics (Torin2) was selected as the first candidate for further evaluation, including testing in an in vivo rodent malaria transmission model. Two 4 mg/kg doses completely blocked parasites ability to infect mosquitoes, and a 2 mg/kg dose gave a partial blockade, confirming the transmission-blocking activity of Torin2. Preliminary data indicate that the Torin2 target in P. falciparum is distinct from the mammalian target, allowing the design of malaria-specific derivatives. Pilot studies between the lead collaborator and NCATS scientists used a gametocyte viability assay, a cellular mTOR assay and an in vivo rodent malaria transmission model to identify new malaria-specific Torin2 analogues. This work resulted in identification of a series of compounds suitable for lead optimization. The project currently is in late-stage lead optimization, with the goal of identifying a compound with single-dose activity against all stages of the disease.